Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/22—Anxiolytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/24—Antidepressants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
  • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
  • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
  • C07D307/81—Radicals substituted by nitrogen atoms not forming part of a nitro radical
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
  • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
  • C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
  • C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
  • C07D319/18—Ethylenedioxybenzenes, not substituted on the hetero ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
  • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
  • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

• the present invention relates to novel piperidine, tetrahydropyridine and piperazine derivatives which are potent serotonin reuptake inhibitors, pharmaceutical compositions containing these compounds and the use thereof for the treatment of disorders or diseases responsive to the inhibition of serotonin re-uptake.
• the compounds of the invention also possess antagonistic activity at 5-HT 1A receptors and are considered to be particularly useful for the treatment of depression.
• Selective serotonin (or 5-HT) reuptake inhibitors such as fluoxetine, paroxetine, sertraline, fluvoxamine and citalopram represent a major step forward in the treatment of depression because they have fewer and less severe side effects compared to first generation antidepressant (tricyclics and non-selective MAO inhibitors).
• first generation antidepressant tricyclics and non-selective MAO inhibitors.
• the side effects associated with first generation antidepressants are such that they cause some patients to withdraw from treatment.
• SSRIs and all other antidepressants currently available suffer from a serious drawback in that several weeks of treatment are necessary to produce the therapeutic effect.
• the late onset of action is a significant problem, particularly in the treatment of patients with severe depression and suicide potential. Further, one in three patients are not responsive to SSRIs.
• pindolol a well known 5-HT 1A receptor and ⁇ - adrenoceptor antagonist
• SSRIs a well known 5-HT 1A receptor and ⁇ - adrenoceptor antagonist
• combined administration of pindolol and an SSRI was shown to have a good effect on patients who were non-responsive to treatment with currently available antidepressants (Artigas F. et al., Arch. Gen. Psychiatry, 1994, 51, p 248-251 and Blier, P. et al., J. Clin. Psychopharmacol. 1995, 15, p 217-222).
• B is an optionally substituted indol-3-yl group and Q is C n H 2n wherein n is 1, 2, 3, 4, 5, or 6 are disclosed.
• These compounds are said to have serotonin agonistic and serotonin antagonistic activity as well as serotonin reuptake inhibiting activity and to be useful as anxiolytics, antidepressants, antipsychotics, antihypertensives, and cerebroprotective agents.
• X is -CH-, -CH 2 -, -NH-, or -CO-; and Ar is
• Y is O, or S
• Z is O, S, or -CH 2 -
• n is 1, 2, or 3.
• a further object of the present invention is to provide a pharmaceutical composition comprising the above compounds as active ingredients.
• the invention then, inter alia, comprises the following alone or in combination:
• B is C,., 0 -alkylene, C 2 . 10 -alkenylene or C 2.10 -alkynylene;
• X is -O-, -S-, or -CR 4 R 5 -;
• Z is -O-, or -S-;
• W is N, C, or CH, and the dotted line is an optional bond
• R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are each independently selected from hydrogen, halogen, trifluoromethyl, C,. 6 -alkyl, C 2 . 6 -alkenyl, C 2 . 6 -alkynyl, C 3 . 7 -cycloalkyl, C 3 _ 7 -cycloalkyl-C,. 6 - alkyl, C,. 6 -alkoxy,
• R 18 is hydrogen, C,. 6 -alkyl, C 2 . 6 -alkenyl, C 2 . 6 -alkynyl, phenyl or phenyl-C,. 6 -alkyl wherein the phenyl groups may be substituted, amino, C,. 6 -alkylamino or C,. 6 -dialkylamino, and
• R is C,. 6 -alkyl, amino, C,. 6 -alkylamino, C,. 6 -dialkylamino, phenyl or phenyl-C,. 6 -alkyl wherein the phenyl groups may be substituted;
• A is a bicyclic ring selected from
• E', E 2 and E 3 are selected from O, S, N, NR", C, CR 12 and CHR 13 , and the dotted line indicates an optional bond, provided that E 2 and E 1 and/or E 3 may not simultaneously be O, or S;
• R 1 , R 2 , R 3 , R 12 , R 13 , R 14 , R 15 , R 16 and R 17 are each independently selected from hydrogen, halogen, trifluoromethyl, C,. 6 -alkyl, C 2 . 6 - alkenyl, C 2.6 -alkynyl, C 3 _ 7 -cycloalkyl, C 3 _ 7 - cycloalkyl-C,_ 6 - alkyl, C,_ 6 -alkoxy, hydroxy, formyl, acyl, amino, C,. 6 -alkylamino, C,. 6 - dialkylamino, acylamino,
• R 19 is C,. 6 -alkyl, amino, C,. 6 -alkylamino, C,. 6 -dialkylamino, phenyl, or phenyl-C,. 6 -alkyl wherein the phenyl groups may be substituted;
• R" is selected from hydrogen, C,_ 6 -alkyl, C 2 . 6 -alkenyl, C 2.6 -alkynyl, C 3 . 7 -cycloalkyl, C 3 . 7 -cycloalkyl-C,. 6 -alkyl, phenyl or phenyl-C,. 6 -alkyl wherein the phenyl group may be substituted, acyl, formyl and -SO 2 -R 19 , wherein R 19 is C, .6 -alkyl, amino, C, .6 -alkylamino, C,. 6 -dialkylamino, phenyl or phenyl-C,. 6 -alkyl wherein the phenyl groups may be substituted;
• R 4 -R 9 is different from hydrogen when A is a group of formula
• the present invention relates to a compound wherein A is selected from the groups of formula (Ic), (Id) and (Ie)
• E', E 2 , E ⁇ and R 14 , R 15 , R 16 and R 17 are as defined in claim 1 and E 5 is N, C or CR 12 .
• the present invention relates to a compound wherein the bicyclic ring A is selected from the groups (If) to (Iq):
• dotted line is an optional bond
• E 6 is O or S
• any of the carbon atoms in the ring may be substituted with any of the substituents defined for R 12 - R 17 above, and wherein the nitrogen atoms in the ring may be substituted with any of the substituents defined above for R 1 ' .
• the present invention relates to a compound wherein A is a group of formula (Ih), (Ij) or (Iq).
• the present invention relates to a compound wherein A is a group of formula (Ih) wherein E 6 is O.
• A is a group of formula (Ih) wherein E 6 is O.
• Such compound is preferably attached to the remainder of the derivative of formula (I) via position 3 in the five-membered ring.
• the present invention relates to a compound wherein A is a group of formula (If). In a final embodiment, the present invention relates to a compound wherein
• B is C,. 6 -alkylene, C,_ 6 -alkenylene, or C 2 . 6 -alkynylene;
• X is -O-, or -S-; and
• Z is -O-, or -S-;
• W is N, C, or CH;
• R 6 , R 7 , R 8 and R 9 are each independently selected from hydrogen, halogen, trifluoromethyl, C,. 6 -alkyl, C,_ 6 -alkoxy, C,. 6 -alkylthio, amino, C,. 6 -alkylamino, C,_ 6 -dialkylamino, phenylamino or phenyl-C,. 6 -alkylamino wherein the phenyl group may be substituted, hydroxy, cyano, nitro, -COOR 18 , -SO--R' 9 and
• R 18 is hydrogen, C,. 6 -alkyl, amino, C,_ 6 -alkylamino or C,. 6 -dialkylamino;
• R' 9 is C,. 6 -alkyl, amino, C,. 6 -alkylamino or C,. 6 -dialkylamino;
• R 11 is selected from hydrogen, C,. 6 -alkyl, phenyl or phenyl-C,. 6 -alkyl wherein the phenyl group may be substituted, acyl, formyl and -SO--R' 9 , wherein R 19 is C,. 6 -alkyl, amino, C j _ 6 - alkylamino or C,_ 6 -dialkylamino.
• Specific compounds of the invention are compounds selected from 1 - [ 1 ,4-Benzodioxan-5 -yl] -4- [ 1 -(inden- 1 -yl)-4-butyl]piperazine, 1 -[ 1 ,4-Benzodioxan-5-yl]-4-[ 1 -(indan- 1 -yl)- 1 -buten-4-yl]piperazine, 1 -[ 1 ,4-Benzodioxan-5-yl]-4-[ 1 -(indan- 1 -yl)-4-butyl]piperazine, l-[l,4-Benzodioxan-5-yl]-4-[2-(5-fluorobenzofuran-3-yl)ethyl]piperazine, l-[l,4-Benzodioxan-5-yl]-4-[3-(6-fluorobenzo[l,2]isoxazol-3-yl)-l-
• Particularly preferred compounds are 1 -[ 1 ,4-Benzodioxan-5-yl]-4-[ 1 -(inden- 1 -yl)-4-butyl]piperazine,
• the invention also relates to a pharmaceutical composition
• a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier or diluent
• the invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof for the preparation of a medicament for the treatment of a disorder or disease responsive to the inhibition of serotonin reuptake and antagonism of 5-HT, A receptors.
• the invention relates to the use of a compound according to the invention or a pharmaceutically acceptable acid addition salt thereof for the preparation of a medicament for the treatment of affective disorders, such as depression, psychosis, anxiety disorders including general anxiety disorder, panic disorder, obsessive compulsive disorder, and eating disorders.
• affective disorders such as depression, psychosis, anxiety disorders including general anxiety disorder, panic disorder, obsessive compulsive disorder, and eating disorders.
• the present invention relates to a method for the treatment of a disorder or disease of living animal body, including a human, which is responsive to the inhibition of serotonin reuptake and antagonism of 5-HT, A receptors comprising administering to such a living animal body, including a human, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof.
• the invention relates to a method for the treatment of affective disorders, such as depression, psychosis, anxiety disorders including general anxiety disorder, panic disorder, obsessive compulsive disorder, and eating disorders comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof to a living animal body, including a human, in need thereof.
• affective disorders such as depression, psychosis, anxiety disorders including general anxiety disorder, panic disorder, obsessive compulsive disorder, and eating disorders
• the compounds of the invention are considered particularly useful as fast onset of action medicaments for the treatment of depression.
• the compounds may also be useful for the treatment of depression in patients who are resistant to treatment with currently available antidepressants.
• the compounds claimed herein are considered particularly useful for the treatment of depression requiring fast onset of antidepressive effect, or a depression which is resistant to other antidepressants.
• Halogen means fluoro, chloro, bromo, or iodo.
• C,. 6 -alkyl means a straight or branched chain of one to six carbon atoms, including for example: methyl, ethyl, propyl, isopropyl, butyl, pentyl and hexyl.
• C 2 . 6 -alkenyl means a chain of from two to six carbon atoms containing one double bond, including for example ethenyl, 1-,2-propenyl, 2-,3-propenyl etc.
• C 2 . 6 -alkynyl means a chain of from two to six carbon atoms containing one triple bond, including for example ethynyl, 1-,2-propynyl, 2-,3-propynyl etc.
• C 0 -alkylene means a chain of one to ten carbon atoms, including for example ethylene, propylene, butylene etc.
• C,. 6 alkylene is an alkylene group as defined above with up to 6 carbon atoms.
• C 2 ., 0 -alkenylene is a chain of two to ten carbon atoms containing one double bond, including for example ethenylene, propenylene, butenylene etc.
• C 2.6 alkenylene is an alkenylene group as defined above containing from 2 to 6 carbon atoms.
• C 2 ., 0 -alkynylene is a chain of from two to ten carbon atoms containing one triple bond, including for example ethynylene, propynylene , butynylene etc.
• C 2 . 6 alkynylene is an alkynylene group as defined above containing from 2 to 6 carbon atoms.
• C 3 . 7 -cycloalkyl means cyclic alkyl of from three to seven carbon atoms, including cyclopropyl, cyclobutyl etc.
• C 3 . 7 -cycloalkyl-C,. 6 -alkyl is composed of C 3 . 7 -cycloalkyl and C,. 6 -alkyl wherein C 3 . 7 - cycloalkyl and C,. 6 -alkyl is as defined above.
• C,. 6 -alkoxy is -O-alkyl where alkyl is as defined above.
• C,. 6 -alkylthio is -S-alkyl where alkyl is as defined above.
• Acyl means -CO-C, .6 -alkyl wherein C,. 6 -alkyl is as defined above.
• Amino means NH 2 .
• C,_ 6 -alkylamino means -NH-C,_ 6 -alkyl
• C, .6 -dialkylamino means -N-(C,_ 6 - alkyl)- where C,_ 6 -alkyl is as defined above.
• C,. 6 -alkoxycarbonylamino means C,. 6 -alkyl-O-CO-NH- wherein C,. 6 -alkyl is as defined above.
• C,. 6 -alkylaminocarbonylamino means C,. 6 -alkyl-NH-CO-NH- wherein C,. 5 -alkyl is as defined above.
• C,. 6 -dialkylaminocarbonylamino means (C,. 6 -alkyl) 2 -NH-CO-NH- wherein C,. 6 -alkyl is as defined above.
• a phenyl group which may be substituted means a phenyl group which may be substituted one or more times with a substituent selected form halogen, trifluoromethyl, cyano, nitro, amino, C,. 6 -alkylamino, C,. 6 -dialkylamino, C, . .-alkyl, C,. 6 -alkoxy and hydroxy.
• organic acid addition salts are those with maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bis-methylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p- aminobenzoic, glutamic, benzenesulfonic, and theophylline acetic acids, as well as the 8- halotheophyllines, for example 8 -bromo theophylline.
• Exemplary of inorganic acid addition salts according to the invention are those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric acids.
• the acid addition salts of the invention are preferably pharmaceutically acceptable salts formed with non-toxic acids.
• the compounds of this invention may exist in unsolvated as well as in solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like.
• the solvated forms are considered equivalent to the unsolvated forms for the purposes of this invention.
• Some of the compounds of the present invention contain chiral centres and such compounds exist in the form of isomers (i.e. enantiomers).
• the invention includes all such isomers and any mixtures thereof including racemic mixtures.
• Racemic forms can be resolved into the optical antipodes by known methods, for example, by separation of diastereomeric salts thereof with an optically active acid, and liberating the optically active amine compound by treatment with a base. Another method for resolving racemates into the optical antipodes is based upon chromatography on an optically active matrix. Racemic compounds of the present invention can thus be resolved into their optical antipodes, e.g., by fractional crystallization of d- or 1- (tartrates, mandelates, or camphorsulphonate) salts for example. The compounds of the present invention may also be resolved by the formation of diastereomeric derivatives. Additional methods for the resolution of optical isomers, known to those skilled in the art, may be used. Such methods include those discussed by J. Jaques, A. Collet, and S. Wilen in "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, New York (1981).
• Optically active compounds can also be prepared from optically active starting materials.
• the compounds of the invention can be prepared by one of the following methods comprising:
• R'-R 3 , X, Y, Z, W, and the dotted line are as defined above with a reagent of formula L-B-A wherein A and B are as defined above and L is a suitable leaving group such as halogen, mesylate, or tosylate; c) reductive alkylation of an amine of formula
• R'-R 3 , B, X, Y, Z, W, and the dotted line are as defined above and A' is a group of formula Ia or lb as defined above in which the dotted line represents a bond, in order to obtain the corresponding 2,3-dihydro derivatives, e.g. 2,3-dihydroindole or 2,3- dihydrobenzofuran;
• R'-R 3 , X,Y, and Z is as defined above with a reagent of formula
• R'-R 3 , B, X, Y, Z, W, and the dotted line are as defined above, and A" is a group selected from a group of formula Ia or lb as defined above in which either E', E 2 , or E 3 is NH with alkylating or acylating reagents of formula R°-L, wherein L is suitable a leaving group such as halogen, mesylate, or tosylate and R° is as defined above for R" but not hydrogen; k) cyclization of compounds of formula XIV,
• R'-R 3 , A, B, W, and the dotted line are as defined above and X' is selected from O or S, with dialkylatng reagents of formula L-Y-L, wherein Y is as defined above and L is a suitable leaving group as described above;
• R'-R 3 , A, B, X, Y, Z, W, and the dotted line are as defined above, and L is a suitable leaving groups as defined above or is an N-imidazolyl or pentafluorophenoxy group in order to obtain the corresponding cyclic oxo-derivatives;
• R'-R 3 , R 6 , A, B, X, Y, Z, W, and the dotted line are as defined above in order to obtain the corresponding cyclic hydroxy derivatives, or by successive dehydration to obtain the corresponding unsaturated ring system;
• R'-R 3 , R 6 -R 8 , A, B, X, Z, W, and the dotted line are as defined above, with cyanating reagents in order to obtain the corresponding cyano derivatives;
• the reduction according to method a) is preferably carried out in an inert organic solvent such as diethyl ether or tetrahydrofuran in the presence of lithium aluminium hydride at reflux temperature.
• an inert organic solvent such as diethyl ether or tetrahydrofuran
• Starting compounds of formula (V), in which A is 3-indolyls are generally prepared from reagents of formula (VI), 1,3-unsubstituted indoles, and oxalyl chloride according to known literature procedures.
• the alkylation according to method b) is conveniently performed in an inert organic solvent such as a suitably boiling alcohol or ketone, preferably in the presence of a base (potassium carbonate or triethylamine) at reflux temperature.
• Arylpiperazine derivatives of formula (VI) are conveniently prepared from the corresponding arylamine according to the method described by Martin et al, J. Med. Chem., 1989, 32, 1052, or the method described by Kruse et al, Rec. Trav. Chim. Pays- Bas, 1988, 107, 303.
• the starting arylamines are either commercially available or are well described in the literature.
• Aryltetrahydropyridine derivatives of formula (VI) are known from literature, cf. US Pat. No. 2,891,066; McElvain et al, J. Amer. Chem. Soc. 1959, 72, 3134.
• the corresponding arylbromide is lithiated with BuLi followed by addition of l-benzyl-4- piperidone.
• Subsequent treatment with acid gives the N-benzyl-aryltetrahydropyridine.
• the benzyl group can be removed by catalytic hydrogenation or by treatment with e.g. ethyl chloroformate to give the corresponding ethyl carbamate followed by acidic or alkaline hydrolysis.
• the starting arylbromides are either commercially available or well described in the literature.
• Reagents of formula L-B-A are either commercially available or can be prepared by literature methods, e.g. from the corresponding carboxylic acid derivative by reduction to the hydroxy derivatives and conversion of the hydroxy group to the group L by conventional methods.
• the reductive alkylation according to method c) is performed by standard literature methods.
• the reaction can be performed in two steps, i.e. coupling of (VI) and the reagent of formula L-B-A by standard methods via the carboxylic acid chloride or by use of coupling reagents such as e.g. dicyclohexylcarbodiimide followed by reduction of the resulting amide with lithium aluminium hydride.
• the reaction can also be performed by a standard one-pot procedure.
• Carboxylic acids or aldehydes of formula K-B'-A are either commercially available or described in the literature.
• Reduction of the double bonds according to method d) is conveniently performed by treatment with diborane or a diborane precursor such as the trimethylamine or dimethylsulfide complex in an inert solvent such as e.g. tetrahydrofuran or dioxane from 0 °C to reflux temperature followed by acid catalyzed hydrolysis of the intermediate borane derivative.
• the reduction can alternatively be performed by treatment with sodium cyanoborohydride in trifluoroacetic acid, by use of magnesium metal, or by catalytic hydrogenation.
• Reduction of the double bonds according to methods e) and f) is most conveniently perfomed by hydrogenation in an alcohol in the presence of a noble metal catalyst, such as e.g. platinum or palladium.
• a noble metal catalyst such as e.g. platinum or palladium.
• halogen substituents according to method g) is conveniently performed by catalytic hydrogenation in an alcohol in the presence of a palladium catalyst or by treatment with ammonium formate in an alcohol at elevated temperatures in the presence of a palladium catalyst.
• the dialkylation of amines according to methods h) and i) is most conveniently performed at elevated temperatures in an inert solvent such as e.g. chlorobenzene, toluene, N- methylpyrrolidone, dimethyl formamide, or acetonitrile.
• the reaction might be performed in the presence of base such as e.g. potassium carbonate or triethylamine.
• base such as e.g. potassium carbonate or triethylamine.
• Starting materials for processes h) and i) are commercially available or can be prepared from commercially available materials using conventional methods.
• the N-alkylation according to method j) is performed in an inert solvent, e.g. an alcohol or ketone, at elevated temperatures in the presence of base, e.g. potassium carbonate or triethylamine, at reflux temperature.
• a phase-transfer reagent can be used.
• Cyclization of keto compounds according to methods 1) or m) is performed, by either base treatment or by employing acidic conditions (See references above in method k, or Thiery, et al, Tetrahedron 1997, 53 (6), 2061-2974).
• Substitution according to method n) can be performed using a Lewis acid, e.g., borontrifluoride etherate or trimethylsilyl trifluoromethanesulphonate and an activated nucleophile (trimethylsilylated compounds).
• a Lewis acid e.g., borontrifluoride etherate or trimethylsilyl trifluoromethanesulphonate and an activated nucleophile (trimethylsilylated compounds).
• Reactions according to method o) is performed by use of standard conditions for nitrile hydrolysis and reductions according to method o) is conveniently performed in an inert solvent such as e.g., diethyl ether or tetrahydrofuran using lithium aluminium hydride or alane.
• an inert solvent such as e.g., diethyl ether or tetrahydrofuran using lithium aluminium hydride or alane.
• Oxidation according to method p) can be performed by using potassium pergamanate in a sodium carbonate solution (A. Salimbeni & E. Manghisi. J. Heterocyclic Chem. 1980, 17:489-492).
• Reduction according to method q) can be performed using lithium aluminium hydride in anhydrous diethyl ether or tetrahydrofuran (Koo, et al., J. Am. Chem. Soc. 1955, 77:5373- 5375).
• the following examples will illustrate the invention further. They are, however, not to be construed as limiting.
• NMR signals corresponding to acidic protons are to some extent omitted. Content of water in crystalline compounds were determined by Karl Fischer titration. Proper elemental analysis for all target compounds were obtained.
• Standard work-up procedures refer to extraction with the indicated organic solvent from proper aqueous solutions, drying of combined organic extracts (anhydrous MgSO 4 or NaSO 4 ), filtering, and evaporation of the solvent in vacuo.
• silica gel of type Kieselgel 60, 40-60 mesh ASTM was used.
• Lithium aluminium hydride (15 g) was suspended in tetrahydrofuran (400 mL) under a nitrogen atmosphere followed by dropwise addition of a solution of methyl 5- fluorobenzofuran-3-carboxylate (58 g) in tetrahydrofuran (300 mL). The temperature increased to 55 °C during the addition. After stirring for 2 h the reaction was quenched successively with water (30 mL), 15% aq. sodium hydroxide (15 mL), and water (75 mL).
• the affinity of the compounds of the invention to 5 -HT 1A receptors was determined by measuring the inhibition of binding of a radioactive ligand at 5-HT, A receptors as described in the following test:
• 3 H-5-carboxamido tryptamine ( 3 H-5-CT) to cloned human 5-HT 1A receptors stably expressed in transfected HeLa cells (HA7) (Fargin, A. et al, J. Biol. Chem., 1989, 264, 14848) is determined in vitro. The assay was performed as a modification of the method described by Harrington, M.A. et al, J. Pharmacol. Exp. Ther., 1994, 268, 1098. Human 5- HT, A receptors (40 ⁇ g of cell homogenate) were incubated for 15 minutes at 37 °C in 50 mM Tris buffer at pH 7.7 in the presence of 3 H-5-CT.
• Non-specific binding was determined by including 10 ⁇ M of metergoline. The reaction was terminated by rapid filtration through Unifilter GF/B filters on a Tomtec Cell Harvester. Filters were counted in a Packard Top Counter. The results obtained are presented in table 1 :
• the 5-HT A antagonistic activity of some of the compounds of the invention has been estimated in vitro at cloned 5-HT 1A receptors stably expressed in transfected HeLa cells (HA7).
• 5-HT A antagonistic activity is estimated by measuring the ability of the compounds to antagonize the 5-HT induced inhibition of forskolin induced cAMP accumulation.
• the assay was performed as a modification of the method described by Pauwels, P.J. et al, Biochem. Pharmacol. 1993, 45, 375. The results obtained are presented in table 3 :
• the antagonistic activity at 5-HT, A receptors of the compounds of the invention will counteract the negative feed back mechanism induced by the inhibition of serotonin reuptake and is thereby expected to improve the effect of the serotonin reuptake inhibiting activity of the compounds of the invention.
• the compounds as claimed herein are therefore considered to be particularly useful as fast onset of action medicaments for the treatment of depression.
• the compounds may also be useful for the treatment of depressions which are non-responsive to cu ⁇ ently available SSRIs.
• Solutions for injections may be prepared by dissolving the active ingredient and possible additives in a part of the solvent for injection, preferably sterile water, adjusting the solution to desired volume, sterilization of the solution and filling in suitable ampules or vials. Any suitable additive conventionally used in the art may be added, such as tonicity agents, preservatives, antioxidants, etc.
• compositions of this invention or those which are manufactured in accordance with this invention may be administered by any suitable route, for example orally in the form of tablets, capsules, powders, syrups, etc., or parenterally in the form of solutions for injection.
• suitable route for example orally in the form of tablets, capsules, powders, syrups, etc.
• parenterally in the form of solutions for injection.
• methods well known in the art may be used, and any pharmaceutically acceptable carriers, diluents, excipients, or other additives normally used in the art may be used.
• the compounds of the invention are administered in unit dosage form containing said compounds in an amount of about 0.01 to 1000 mg.
• the total daily dose is usually in the range of about 0.05 - 500 mg, and most preferably about 0.1 to 50 mg of the active compound of the invention.

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• 2000
  • 2000-01-17 AR ARP000100197A patent/AR022303A1/es not_active Application Discontinuation
  • 2000-01-21 CN CN00805148A patent/CN1344265A/zh active Pending
  • 2000-01-21 MX MXPA01007226A patent/MXPA01007226A/es not_active Application Discontinuation
  • 2000-01-21 AT AT00901481T patent/ATE263763T1/de not_active IP Right Cessation
  • 2000-01-21 EA EA200100798A patent/EA200100798A1/ru unknown
  • 2000-01-21 BR BR0009007-7A patent/BR0009007A/pt not_active IP Right Cessation
  • 2000-01-21 AU AU22781/00A patent/AU767377B2/en not_active Ceased
  • 2000-01-21 KR KR1020017009122A patent/KR20010101606A/ko not_active Application Discontinuation
  • 2000-01-21 IL IL14411300A patent/IL144113A0/xx unknown
  • 2000-01-21 DE DE60009663T patent/DE60009663T2/de not_active Expired - Fee Related
  • 2000-01-21 CA CA002361059A patent/CA2361059A1/en not_active Abandoned
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  • 2000-01-21 WO PCT/DK2000/000026 patent/WO2000043382A1/en not_active Application Discontinuation
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• 2001
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• 2002
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